The goal of this project is to understand the role of mitochondrial aldehyde dehydrogenase 1B1 (ALDH1B1) in ethanol- induced colorectal carcinogenesis. Chronic alcohol abuse elicits a plethora of pathological outcomes including damage to the liver, brain and other organs, such as the colorectum. A causal relationship between alcohol consumption and colorectal cancer has been established by the International Agency for Research on Cancer (IARC). Several meta-analyses suggest a linear relationship between alcohol consumption and colorectal cancer. Most of the pathological effects of ethanol are attributed to its reactive metabolites. Ethanol-derived acetaldehyde, responsible for some of the major toxic effects of alcohol consumption, is metabolized to acetate by aldehyde dehydrogenases (ALDHs), mostly by mitochondrial ALDH2 and, to a lesser extent, by cytosolic ALDH1A1. We have recently shown that ALDH1B1, which shares a 72% identical amino acid sequence with ALDH2, (a) has a high affinity for acetaldehyde and retinaldehyde, and (b) is a potential biomarker and participant in human colorectal cancer. Together, these data support our novel hypothesis that acetaldehyde/retinaldehyde- metabolizing enzyme ALDH1B1 is a key player in the development of ethanol-induced colorectal cancer. We therefore propose to: 1) determine the role of ALDH1B1 in colorectal cancer development by using Aldh1b1 knockout mice and established animal models for ethanol-induced colorectal cancer, and 2) elucidate the role of ALDH1B1 as a biomarker for alcohol-induced colorectal cancer in humans by immunohistochemical analysis of colorectal cancer samples from alcoholic and non-alcoholic patients. Findings from these investigations will, for the first time, delineate the role of the second mitochondrial ALDH (ALDH1B1) in ethanol-induced colorectal cancer in both mice and humans. Most importantly, these studies are expected to validate the use of ALDH1B1 as an early and effective diagnostic marker for colon cancer and as a therapeutic target for the prevention or treatment of ethanol-induced colon cancer, and potentially other alcohol-related cancers in the future.